Junhui Yuan

Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.

Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation

Objective: To identify the clinical features of Japanese patients with suspected hereditary sensory and autonomic neuropathy (HSAN) on the basis of genetic diagnoses. Methods: On the basis of clinical, in vivo electrophysiologic, and pathologic findings, 9 Japanese patients with sensory and autonomic nervous dysfunctions were selected. Eleven known HSAN disease–causing genes and 5 related genes were screened using a next-generation sequencer. Results: A homozygous mutation, c.3993delGinsTT, was identified in exon 22 of SCN9A from 2 patients/families. The clinical phenotype was characterized by adolescent or congenital onset with loss of pain and temperature sensation, autonomic nervous dysfunctions, hearing loss, and hyposmia. Subsequently, this mutation was discovered in one of patient 1s sisters, who also exhibited sensory and autonomic nervous system dysfunctions, with recurrent fractures being the most predominant feature. Nerve conduction studies revealed definite asymmetric sensory nerve involvement in patient 1. In addition, sural nerve pathologic findings showed loss of large myelinated fibers in patient 1, whereas the younger patient showed normal sural nerve pathology. Conclusions: We identified a novel homozygous mutation in SCN9A from 2 Japanese families with autosomal recessive HSAN. This loss-of-function SCN9A mutation results in disturbances in the sensory, olfactory, and autonomic nervous systems. We propose that SCN9A mutation results in the new entity of HSAN type IID, with additional symptoms including hyposmia, hearing loss, bone dysplasia, and hypogeusia.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next‐generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.

Mitochondrial myopathy with autophagic vacuoles in patients with the m.8344A>G mutation

Background and aims In mitochondrial myopathy, autophagy is presumed to play an important role in mitochondrial dysfunction. Rimmed vacuoles (RVs), a sign of autophagy, can be seen as a secondary phenomenon in muscle ragged-red fibres (RRFs), whereas the uncommon presentation is that some fibres contain RVs, but without any mitochondrial abnormalities. To investigate the pathogenesis beneath this pathological phenomenon. Methods We reviewed 783 skeletal muscle specimens and selected five obtained from patients with suspected mitochondrial myopathy, characterised by clearly visible autophagic vacuoles in non-RRFs, besides the coexistence of RRFs and cytochrome oxidase-negative fibres. Immunohistochemical staining with LC-3, and electron microscopy studies were performed. Using resequencing microarray and a next-generation sequencing system, the mitochondrial DNA was screened for mutations and the heteroplasmic level was measured in skeletal muscle and blood. Results Muscle fibres with RVs and RRFs, as well as some morphologically normal fibres, stained strongly for LC-3. Electron microscopy disclosed significant abnormal mitochondrial proliferation and existence of autophagic vacuoles. After mutation screening, m.8344A>G in the tRNALys gene was detected in two patients. The heteroplasmy of mutated G was 45.1% in skeletal muscle and 17.8% in blood in patient 1; patient 2 exhibited 80.3% mutated G in skeletal muscle and 25.2% in blood. Conclusions These findings demonstrate a new pathological phenotype for the m.8344A>G mutation- related disease and also provide pathological evidence of a correlation between mitochondrial abnormalities and autophagy.

New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan

Objective: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. Methods: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. Results: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff–positive macrophages and 2–7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. Conclusions: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy

Higuchi et al. identify recessive mutations in the mitochondrial gene, cytochrome c oxidase assembly factor 7 (COA7) in four unrelated patients with an axonal-type motor and sensory neuropathy with ataxia. Genetic, histopathological, radiological and functional data support a causative role for loss-of-function COA7 mutations in the observed phenotype.

Clinical diversity caused by novel IGHMBP2 variants

Immunoglobulin helicase μ-binding protein 2 (IGHMBP2) gene is responsible for Charcot–Marie–Tooth disease (CMT) type 2S and spinal muscular atrophy with respiratory distress type 1 (SMARD1). From June 2014 to December 2015, we collected 408 cases, who referred to our genetic laboratory for genetic analysis, suspected with CMT disease or other inherited peripheral neuropathies (IPNs) on the basis of clinical manifestations and electrophysiological studies. Mutation screening was performed using Ion AmpliSeq Custom Panels, which comprise 72 disease-causing or candidate genes of IPNs. We identified novel homozygous or compound heterozygous variants of IGHMBP2 in four patients. Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies, whereas the other case was diagnosed with SMARD1, manifesting as low birth weight, weak cry, reduced spontaneous movement and developed respiratory distress 4 months after birth. We present the original report of CMT type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for ~1.6% of axonal CMT in our cohort.

Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants

Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot‐Marie‐Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.

Arthropathy-related pain in a patient with congenital impairment of pain sensation due to hereditary sensory and autonomic neuropathy type II with a rare mutation in the WNK1/HSN2 gene: a case report

BackgroundHereditary sensory and autonomic neuropathy (HSAN) type II with WNK1/HSN2 gene mutation is a rare disease characterized by early-onset demyelination sensory loss and skin ulceration. To the best of our knowledge, no cases of an autonomic disorder have been reported clearly in a patient with WNK/HSN2 gene mutation and only one case of a Japanese patient with the WNK/HSN2 gene mutation of HSAN type II was previously reported.Case presentationHere we describe a 54-year-old woman who had an early childhood onset of insensitivity to pain; superficial, vibration, and proprioception sensation disturbances; and several symptoms of autonomic failure (e.g., orthostatic hypotension, fluctuation in body temperature, and lack of urge to defecate). Genetic analyses revealed compound homozygous mutations in the WNK1/HSN2 gene (c.3237_3238insT; p.Asp1080fsX1). The patient demonstrated sensory loss in the “stocking and glove distribution” but could perceive visceral pain, such as menstrual or gastroenteritis pain. She experienced frequent fainting episodes. She had undergone exenteration of the left metatarsal because of metatarsal osteomyelitis at 18 years. Sural nerve biopsy revealed a severe loss of myelinated and unmyelinated nerves. She complained of severe pain in multiple joints, even on having pain impairment. Although non-steroidal anti-inflammatory drugs are generally more effective than acetaminophen for arthritis, in our case, they were ineffective and acetaminophen (2400 mg/day) adequately controlled her pain and improved quality of life. Over 3 months, the numerical rating scale, pain interference scale of the Brief Pain Inventory, and the Pain Catastrophizing Scale decreased from 6/10 to 3/10, from 52/70 to 20/70, and from 22/52 to 3/52 points, respectively.ConclusionsThis is the second reported case of a Japanese patient with WNK/HSN2 gene mutation of HSAN type II and the first reported case of an autonomic disorder in a patient with the WNK/HSN2 gene mutation. Acetaminophen adequately controlled arthropathy related pain in a patient with congenital impairment of pain sensation.

A case of Andersen–Tawil syndrome presenting periodic paralysis exacerbated by acetazolamide

Andersen–Tawil syndrome (ATS) is a rare autosomal dominant disorder described first by Andersen et al. [1] and Tawil et al. [2]. It has the clinical triad of periodic paralysis (PP), ventricular arrhythmia and dysmorphic features. Patientswith ATS, unlike thosewith other types of PP, may develop fatal ventricular arrhythmia, although the occurrence of this is rare [3]. Plaster et al. identified a heterozygous mutation of KCNJ2 gene encoding an inward-rectifying potassium channel Kir2.1 in ATS patients [4]. Very recently, a mutation in the KCNJ5 gene encoding Kir3.4 was also reported in ATS [5]. Since the detection of genetic mutations, genetically diagnosed ATS has been revealed to be heterogeneous in terms of its phenotypes, with some patients exhibiting only one or two symptoms of the triad [6]. Therefore, the diagnosis of ATS on clinical manifestation is sometimes difficult. For the prevention of PP, there has been no established treatment as yet, but acetazolamide has been reported to be effective in some ATS patients [7]. Here, we report a case of genetically diagnosed ATS whose PP was exacerbated by acetazolamide. A 31-year-old Japanesemanwas admitted to our hospital because of deteriorating weakness of his limbs. He had first experiencedweakness of his limbs 10 years earlier, and had been diagnosed as having hypokalemic PP, because a low serum potassium concentration was observed (2.0 mEq/L; normal range 3.5–5.0 mEq/L). Thereafter, he had experienced mild weakness several times that had usually recovered within a few days. However, his muscle weakness worsened gradually over several days in this recurrence. There was no family history of PP, but his father died suddenly in a bath at the age of 49 years by an unknown cause. Neurological examination on admission revealed generalized muscular weakness predominantly in the proximal extremities and decreased tendon reflexes. There were no obvious facial or skeletal dysmorphic features. Laboratory tests showed slightly elevated levels of creatine kinase (299 U/L; normal range 62–287 U/L). His serum potassium concentration (4.0 mEq/L) and thyroid function were normal. Electrocardiography demonstrated no apparent arrhythmia, QT prolongation (corrected QT interval: 402 ms) or U-waves. Both a nerve conduction study and needle electromyography revealed normal findings. A prolonged exercise test exhibited a maximal 33.1% decrement at 44 min after exercise in the compound muscle action potential of the abductor digiti minimi muscle, strongly indicating primary PP in this